Using a combination of quantum-mechanical and classical methodology, we are investigating base catalyzed amide hydrolysis. This reaction is prototypical for many enzymatic peptide cleavage processes and a thorough study can therefore enhance our understanding of some important biological processes. We have performed high level ab initio calculations to obtain an accurate description of the gas phase reaction path and the reaction energetics for small amides. We have carried out Monte Carlo simulations for the reactants placed in a bath of explicit water molecules to calculate solvent effects on this reaction. Using statistical perturbation theory and a protocol introduced by Jorgensen, we have calculated the potentials of mean force along the predetermined reaction coordinate. Some important results include the observation of a significant solvent- induced barrier towards formation of the tetrahedral intermediate (TET), and a remarkable shift of the transition state towards TET breakdown. Similar calculations have been performed for the TET formation step in the corresponding enzymatic reaction (Trypsin). In general, we have achieved good agreement with the available experimental data. We plan to extend our studies to investigate (1) explicit polarization, (2) a fully coupled QM/MM representation of the system. Both enhancements in the underlying theoretical model are expected to improve the accuracy of the results, and their importance can be assessed. The graphics facilities of the Computer Graphics Laboratory at UCSF have been used extensively in the course of our studies. Computer programs including MidasPlus (from CGL) and CHEMCAM (from myself) have prove very helpful to visualize various aspects of the reaction. The use of the CGL facilities is essential for successful completion of the current project.